Lon S. Schneider, MD, MS - US grants

This is a proposal for a random assignment, double-blind, placebo- controlled clinical trial of carbamazepine in 66 probable and possible AD outpatients with clinically significant behavioral disorders. The duration of study is six weeks with a 10 to 7 day screening period (run- in). Subjects will be assessed for efficacy at biweekly intervals using validated instruments by raters blind to treatment condition. A clinical monitor who is open to mediation status will evaluate subjects weekly to enhance safety. Subjects originally assigned to placebo will be offered an open six week trial of medication under similar study conditions. After the six week trial, there will be an open, uncontrolled, continuation phase of 24 week's duration to assess safety, drug autometabolism, and continuing efficacy. Patients will be seen at monthly intervals for follow-up. The objective of this study is to compare carbamazepine (400 to 300 mg/d) to a placebo control in terms of efficacy and side effects in treating agitated AD patients. Measures of efficacy include the Brief psychiatric Rating Scale (BPRS), Clinical Global Improvement Scale (CGI), Hamilton Rating Scale for Depression, Relatives' Assessment of Global Symptomatology-Elderly (RAGS-E), the Physical Self-Maintenance Scale and Instrumental Activities of Daily Living (PSMS/IADL). The primary criterion for clinical response is a greater than or equal to 30% improvement on the agitation factor of the BPRS, and a 'much improved' rating on the CGI. A minimum effect size for carbamazepine is defined (r=0.18). A secondary objective is to replicate a prior observation that platelet 3H-imipramine binding B(max) is decreased, and MAO activity is relatively decreased in Alzheimer's patients with symptomatic behaviors compared to Alzheimer's disease patients without symptomatic behaviors.

ADRC Subcore in Clinical Pharmacology. The clinical neuropharmacology subcore for the Alzheimer's Disease Research Center Consortium of Los Angeles and Orange Counties (ADRC) maintains an infrastructure to support, strengthen, and facilitate clinical pharmacological research in the ADRC. The core improves the quality of clinical research and hypothesis testing; increases the kinds of clinical studies performed; and increases and expedites patient access to studies at the ADRC. The resources of the core are utilized by and benefit individual ongoing projects and investigators and foster new meritorious clinical research projects. The core is based at the Tower Hall Clinical on the USC School of Medicine campus, and consists of a program director, Dr. Schneider, geriatric physicians, a bilingual clinical psychologist, a research nurse/coordinator, and administrative assistant, and research assistants. Specific goals include the performance of pilot or preliminary clinical pharmacological investigations to test new hypotheses; enhancement of recruitment of ethnic minority subjects to clinical investigations; conducting controlled studies of treatments for behavioral symptoms in Alzheimer's dementia; planning and developing future pharmacological work. The core has been in operation only since September, 1992. Current objectives are: To further develop the administrative structure to efficiently coordinate and develop clinical pharmacological research, involving comprehensive documentation, evaluation of patients, assessing the validity and reliability of evaluation methods and results; and providing long-term follow-up of former and current research subjects to facilitate clinical investigations and evaluation of various therapies and interventions directed toward treatment an management of AD patients, including pilot, phase I and phase II clinical evaluations; characterization of the pharmacokinetics, including the design and implementation of dose escalation and safety studies; to enhance recruitment of ethnic-minority subjects to the pharmacology core, ADRC Clinical Core, Spanish-speaking program, and to the satellite program: to undertake pilot studies of both cognitively and behavioral active medications in AD patients with symptomatic behaviors such as agitation, psychosis and major depression; to provide consultative and educational resources on investigational medications and the clinical pharmacology of AD to other ADRC components, to the community; and to cooperate with other ADRC clinical and basic research programs in the acquisition of research specimens and measures.

[unreadable] DESCRIPTION (provided by applicant): Depression in the context of Alzheimer's disease (AD) is a significant public health problem with serious adverse consequences for patients and their caregivers. There has been little research into the course or treatment of depression associated with AD. This is in part due to the absence of validated operational criteria for defining depression in AD. Recently, NIMH convened an expert consensus panel to develop draft criteria for depression of Alzheimer's disease (dAD) and to establish research priorities in this area. These criteria are intended to facilitate further studies of the course and treatment of depression in AD. The first aim of the proposed multicenter study is to determine whether individuals with dAD respond to antidepressant treatment using the medication sertraline in a 12-week randomized, controlled, double blind trial. The second aim is to establish whether earlier treatment of depression in AD affects critical non-mood outcomes such as cognition, quality of life, activities of daily living and caregiver variables, over 24 weeks. The third aim is to validate the dAD syndrome by evaluating its course and response to treatment in comparison to other diagnostic conceptualizations of depression in AD, over six months. These aims are consistent with priorities articulated by the NIMH expert consensus panel. 130 patients meeting criteria for dAD, and their caregivers, will be recruited into the study at five clinical centers: Johns Hopkins, University of Southern California, University of Rochester, University of Pennsylvania, and Medical University of South Carolina. The study will be coordinated by the Johns Hopkins Center for Clinical Trials. After detailed baseline characterization participants will be randomized to treatment with sertraline or placebo for at least twelve weeks and followed for up to 24 weeks. All patients and caregivers will receive psychosocial interventions for Alzheimer's and depression. Patient outcomes will include: global improvement of the depressive disturbance, ratings on a depression scale, quality of life, cognitive functioning, activities of daily living, behavioral disturbance, and adverse events. Caregiver outcomes will include: depression, quality of life, and care giving burden. Regarding the first study aim, analyses will compare the two treatment groups on patient mood outcomes in the first twelve weeks. Regarding the second study aim, analyses will compare the two treatment groups on the trajectories of patient critical AD patient outcomes (cognition, functioning, quality of life, behavior) and of caregiver outcomes over 24 weeks. Regarding the third aim, analyses will examine the longitudinal course of depressive symptoms and of depressive syndromes in the context of Alzheimer's using three different syndromic definitions: dAD, DSM-IV, and "Alzheimer's Associated Affective disorder" derived empirically. The predictive validity of defining depression in AD using a symptom scale or each of these syndromes will be assessed longitudinally against the various study outcomes, and against efficacy of response to antidepressant treatment. [unreadable] [unreadable]

Abbreviations; Adult; Advisory Committees; Age; Aging; Alzheimer's Disease; Antipsychotic Agents; Autopsy; Behavioral; Biocompatible Materials; Biological; Brain; brain research; California; cardiovascular risk factor; central retinal artery; Cerebrovascular Disorders; Chinese American; Chinese People; Citalopram; Clinical; Clinical Research; clinical research site; Clinical Trials; cognitive change; cohort; cooperative study; Data; data acquisition; Data Set; Dementia; diagnosis evaluation; Educational aspects; Effectiveness of Interventions; Elderly; eligible participant; Enrollment; Evaluation; Eye; Finches; follow-up; Future; Genetic Materials; genome wide association study; Glossary; Guidelines; Health Sciences; Impaired cognition; Industry; Intervention Trial; intima media; Knowledge; Latino; Longitudinal Studies; Los Angeles; Magnetic Resonance Imaging; Mental Depression; mild cognitive impairment; modifiable risk; National Institute on Aging; neuroimaging; neuropathology; neuropsychological; Participant; Photography; Pilot Projects; Population; Population Study; Program Research Project Grants; programs; public health medicine (field); Recruitment Activity; Registries; Rehabilitation Centers; Research; Research Project Grants; research study; Research Support; Resources; Risk Factors; selective androgen receptor modulator; Selective Estrogen Receptor Modulators; Site; Source; Thick; Tissues; Underserved Population; United States National Institutes of Health; Venous

DESCRIPTION (provided by applicant): Selective estrogen receptor-2 (ER2) targeting may be a novel therapeutic target for the development of therapies for a range of conditions including cognitive impairment and age- related ovarian failure (menopause). There are plausible mechanisms by which ER2 receptor stimulation could lead to improved cognition, feelings of well being, reduced risks for cognitive impairment, and improved vasomotor symptoms. A formulation composed of rationally-selected ER2-selective phytoestrogens (phytoSERMs) was developed that provides a greater effect than the various nutraceuticals that are mixed with both ER1 and ER2 selective components. This new formulation is composed of rationally-defined content that induces synergistic rather than antagonistic effects on estrogen receptors and could likely generate salutary therapeutic effects. The formulation enhances ER2 responses by adding equol to genistein and daidzein moderating potential influences of inter- individual differences in the production of equol. Three major potential advantages of the formulation are: (1) reduction of antagonistic interactions that occur in complex soy-derived isoflavone preparations;(2) minimization of adverse effects associated with ER1 activation in reproductive tissues;(3) potential health benefits in pathologic conditions mediated by ER2. Thus, it may serve as an alternative to current estrogen therapies. We are proposing a phase I to IIa pilot development program for this ER2 specific phytoSERM combination for post-menopausal women in the 50 year-old range as the first to human studies. The phase I bridging study uses ascending doses in 3 consecutive panels of 9 participants to assess tolerability, pharmacokinetics, and potential safety with 4 weeks exposures. The phase IIa proof of concept dose-ranging, placebo-controlled trial will assess tolerability, safety, and potential efficacy over 12 weeks. Given that soy isoflavone extracts are available as dietary supplements, and that the compounds are 'generally recognized as safe'(GRAS, under FDA regulations), we expect this phytoSERM combination to be very well tolerated with a benign adverse event profile over 12 weeks. Because soy derived isoflavones sold as dietary supplements were not subject to formal drug development, and that this is a new combination of phytoSERMs, we believe that a careful, stepwise development approach for the phytoSERMs will provide systematic information, better benefit clinical knowledge, and provide a platform for future development. PUBLIC HEALTH RELEVANCE: One of the largest unmet needs in menopausal women's health is an estrogen therapy that is both safe and effective. We have developed a formulation of phytoestrogenic molecules, that we term PhytoSERMs, which targets estrogen receptor beta. This study will determine the best dose, safety and tolerance of PhytoSERMs in peri to menopausal women experiencing hot flashes. We will also conduct a pilot analysis to determine the efficacy of PhytoSERMs to significantly reduce hot flashes.

DESCRIPTION (provided by applicant): Phase 2 and 3 clinical trials in Alzheimer disease (AD) and mild cognitive impairment (MCI) have been generally unsuccessful over the past decades. Efficacy mainly has been demonstrated in trials of 6 months or less, only with cholinesterase inhibitors for mild AD, and not in MCI or longer-term trials. Recent therapies based on the neuropathology of AD have not demonstrated efficacy in 18 month trials. Although this may reflect lack of knowledge of the biological targets and consequently the testing of ineffective drugs, it also reflects inadequacies of trials methods such that a modestly effective drug - if tested - may likely not be recognized as effective. In particular, the trials appear to choose patient samples based on assumptions about desired characteristics and outcomes that may not be valid because they are based on selected experiences from previous individual trials, further raising questions about design and validity. This project's broad, long-term objectives are to develop rational bases for designing pilot and phase 2 trials based on systematic evaluation of previous trials and testing design features prospectively. A broader goal is to encourage, complement, and accelerate the process of testing new and innovative treatments by providing models and simulations for clinical trials methods and designs. The research design and methods for achieving the objectives involves integrating patient data from 14 clinical trials and studies from the NIA's ADCS and ADNI over the last decade - including over 5200 followed from 1 to 4 years - into a common database. This allows for prospective analyses using hypothesis-based statistical techniques including simulations to better understand design parameters, outcomes, and to design better and more clinically relevant trials that would have the ability to detect change. The ADCS studies have inherent similarities that allow for combining, including common data base structures, outcomes, sites, training, and procedures. An expert steering committee formulates guiding principles and hypothesis-based research plans. Specific protocols address issues such as selection criteria, predictors of decline, and simulations to assess new trials designs. For example, we will examine the effects on outcomes of selecting patients for trials based on concomitant medication or severity using regression estimates and regression to the mean adjusted estimates, and follow this with trials simulations to empirically test validity and to plan future trials. Results of this research will have broad and lasting impact on trials designs in this therapeutic area, and especially on early phase trials in that designs can be tested and refined prior to implementing trials. The project is highly innovative in that it provides new approaches in this research area to examine the underlying patient data from numerous studies, and takes advantage of the rich database to empirically probe the assumptions under which current trials have been instigated. This will lead to improvement in trials methods and increase the likelihood for identifying effective treatments earlier in development.

DESCRIPTION (provided by applicant): Selective estrogen receptor-2 (ER2) targeting may be a novel therapeutic target for the development of therapies for a range of conditions including cognitive impairment and age- related ovarian failure (menopause). There are plausible mechanisms by which ER2 receptor stimulation could lead to improved cognition, feelings of well being, reduced risks for cognitive impairment, and improved vasomotor symptoms. A formulation composed of rationally-selected ER2-selective phytoestrogens (phytoSERMs) was developed that provides a greater effect than the various nutraceuticals that are mixed with both ER1 and ER2 selective components. This new formulation is composed of rationally-defined content that induces synergistic rather than antagonistic effects on estrogen receptors and could likely generate salutary therapeutic effects. The formulation enhances ER2 responses by adding equol to genistein and daidzein moderating potential influences of inter- individual differences in the production of equol. Three major potential advantages of the formulation are: (1) reduction of antagonistic interactions that occur in complex soy-derived isoflavone preparations; (2) minimization of adverse effects associated with ER1 activation in reproductive tissues; (3) potential health benefits in pathologic conditions mediated by ER2. Thus, it may serve as an alternative to current estrogen therapies. We are proposing a phase I to IIa pilot development program for this ER2 specific phytoSERM combination for post-menopausal women in the 50 year-old range as the first to human studies. The phase I bridging study uses ascending doses in 3 consecutive panels of 9 participants to assess tolerability, pharmacokinetics, and potential safety with 4 weeks exposures. The phase IIa proof of concept dose-ranging, placebo-controlled trial will assess tolerability, safety, and potential efficacy over 12 weeks. Given that soy isoflavone extracts are available as dietary supplements, and that the compounds are 'generally recognized as safe' (GRAS, under FDA regulations), we expect this phytoSERM combination to be very well tolerated with a benign adverse event profile over 12 weeks. Because soy derived isoflavones sold as dietary supplements were not subject to formal drug development, and that this is a new combination of phytoSERMs, we believe that a careful, stepwise development approach for the phytoSERMs will provide systematic information, better benefit clinical knowledge, and provide a platform for future development. PUBLIC HEALTH RELEVANCE: One of the largest unmet needs in menopausal women's health is an estrogen therapy that is both safe and effective. We have developed a formulation of phytoestrogenic molecules, that we term PhytoSERMs, which targets estrogen receptor beta. This study will determine the best dose, safety and tolerance of PhytoSERMs in peri to menopausal women experiencing hot flashes. We will also conduct a pilot analysis to determine the efficacy of PhytoSERMs to significantly reduce hot flashes.

DESCRIPTION (provided by applicant): Phase 2 and 3 clinical trials in Alzheimer disease (AD) and mild cognitive impairment (MCI) have been generally unsuccessful over the past decades. Efficacy mainly has been demonstrated in trials of 6 months or less, only with cholinesterase inhibitors for mild AD, and not in MCI or longer-term trials. Recent therapies based on the neuropathology of AD have not demonstrated efficacy in 18 month trials. Although this may reflect lack of knowledge of the biological targets and consequently the testing of ineffective drugs, it also reflects inadequacies of trials methods such that a modestly effective drug - if tested - may likely not be recognized as effective. In particular, the trials appear to choose patient samples based on assumptions about desired characteristics and outcomes that may not be valid because they are based on selected experiences from previous individual trials, further raising questions about design and validity. This project's broad, long-term objectives are to develop rational bases for designing pilot and phase 2 trials based on systematic evaluation of previous trials and testing design features prospectively. A broader goal is to encourage, complement, and accelerate the process of testing new and innovative treatments by providing models and simulations for clinical trials methods and designs. The research design and methods for achieving the objectives involves integrating patient data from 14 clinical trials and studies from the NIA's ADCS and ADNI over the last decade - including over 5200 followed from 1 to 4 years - into a common database. This allows for prospective analyses using hypothesis-based statistical techniques including simulations to better understand design parameters, outcomes, and to design better and more clinically relevant trials that would have the ability to detect change. The ADCS studies have inherent similarities that allow for combining, including common data base structures, outcomes, sites, training, and procedures. An expert steering committee formulates guiding principles and hypothesis-based research plans. Specific protocols address issues such as selection criteria, predictors of decline, and simulations to assess new trials designs. For example, we will examine the effects on outcomes of selecting patients for trials based on concomitant medication or severity using regression estimates and regression to the mean adjusted estimates, and follow this with trials simulations to empirically test validity and to plan future trials. Results of this research will have broad and lasting impact on trials designs in this therapeutic area, and especially on early phase trials in that designs can be tested and refined prior to implementing trials. The project is highly innovative in that it provides new approaches in this research area to examine the underlying patient data from numerous studies, and takes advantage of the rich database to empirically probe the assumptions under which current trials have been instigated. This will lead to improvement in trials methods and increase the likelihood for identifying effective treatments earlier in development. PUBLIC HEALTH RELEVANCE: The results of this research will have a broad and lasting impact on trial designs for Alzheimer disease, mild cognitive impairment, and neurodegenerative disorders, and trials in which cognitive improvement is a targeted outcome. It will address important issues in the assumptions underlying the design decisions. This will lead to better understanding and improvement in the methods for future clinical trials and improve the likelihood for identifying effective treatments, as well as identifying ineffective treatments earlier in development.

DESCRIPTION: Therapeutics to prevent, delay and treat Alzheimer's disease (AD) remains to be achieved. Currently, over 5 million Americans are diagnosed with AD and the number is projected to increase to 11-16 million within two decades unless therapeutic advances are made. Proposed herein is a regenerative medicine, systems biology approach that targets the regenerative system of the brain while simultaneously activating systems to reduce AD pathology. Allopregnanolone (Allo) is a pleiotropic regenerative therapeutic that promotes neurogenesis and restores cognitive function in both a preclinical AD model and wild type aged mice and reduces pathology in a preclinical AD model. Further Allo promotes regeneration of human neural stem cells. Allo is a neurosteroid endogenous to the brain of low molecular weight and blood brain barrier penetrant with abundant existing safety data in animals and humans. Its mechanisms of neural stem cell proliferation and restoration of cognitive function are well characterized and consistent with well-described neurogenic mechanisms in brain. Allo reduces AD pathology via well-established pathways upstream to Abeta generation to prevent the generation of Abeta while also decreasing inflammation and increasing myelin generation. Based on a foundation of preclinical discovery (ADDF), translational research (NIA U01), clinical development with NIA USC ADRC and FDA assessment, we propose a Phase 1 multiple ascending dose clinical trial of four Allo doses administered in a regenerative regimen of once-per-week for twelve weeks to establish a safe and tolerated dose of Allo necessary to advance to a Phase 2 efficacy trial. To achieve this goal, two specific aims are proposed. Aim 1 is designed to conduct a Phase 1 multiple ascending dose trial of Allo in participants diagnosed with MCI due to AD and early AD. Primary safety objectives are to determine: 1) maximally tolerated dose; 2) incidence and severity of treatment emergent adverse events; 3) designated medical events; 4) clinically important changes in safety assessments including amyloid related imaging abnormalities (ARIA). Aim 2 is designed to conduct exploratory safety and feasibility analyses regarding the effect of once- per-week-exposure for 12 weeks to Allo at 4 doses on cognitive function and MRI-based biomarkers. Secondary objectives are to: 1) assess potential short-term effects of Allo dosing on cognition and MRI indicators of AD; 2) inform subsequent phase 2 proof of concept trial with MRI-based biomarkers of regenerative efficacy. A multidisciplinary team of investigators with expertise in Allo systems biology and translational research and clinical trials for AD therapeutics are committed to the project. Trial outcomes will provide: 1) an estimated safe and well-tolerated dose of Allo; 2) parameter estimates for cognitive efficacy to advance to a Phase 2 proof of concept trial of Allo; and 3) parameter estimates for MRI-based biomarkers. This proposal meets the objectives of RFA-AG-13-016.

Drug development in Alzheimer's disease (AD) requires a considerable investment of time and re- sources, often with little reward as the vast majority of medications ultimately prove unsuccessful. Drug repur- posing, in which medications that already have been approved for treatment are evaluated for therapeutic effects in other disorders, has the potential to markedly increase the number of agents in the drug development pipeline but requires methods for effective screening of candidate medications for activity. In silico or computational ap- proaches to medication screening are rapidly growing, and have been successful in illnesses such as cancer, but their application to AD remains understudied. There is also intense interest in drug repurposing approaches that will utilize the vast amounts of clinical data that are being collected from epidemiological studies and clinical encounters documented through electronic health records (EHRs). In this proposal, we present a novel approach to drug repurposing that uses large-scale data mining (i.e., pattern recognition) algorithms applied to concurrent medication taken by participants in AD clinical trials and in Medicare administrative data to determine which of these medications show potential therapeutic bene?ts. With over 30 years of AD clinical trial data available to us through a recently developed meta-database and 10 years of prescription data available through Medicare Part D, the administration of concurrent medications to patients as part of their routine clinical care constitutes a large- scale natural experiment. This information can be harnessed for AD treatment discovery if appropriate methods can be developed to detect effects on disease progression within this high-dimensional data. Data mining al- gorithms that discover patterns of associations in data, rather than testing predetermined hypotheses, are well suited to application in large-scale screening for drug repurposing. Using our meta-database and Medicare data, we will be able to evaluate most of the more than 6,000 currently available prescription medications for ef?cacy in AD using well-accepted endpoints for measuring disease progression. The discovery phase will be followed by a validation phase of promising candidate medications in independent data sets, as well as identi?cation of plausible gene targets for each medication from the biomedical literature. This study will set the groundwork for a series of follow-up in vivo studies to conclusively demonstrate effects of selected medications for AD, expanding the current armamentarium for treating this common and debilitating disorder.

PROJECT SUMMARY It has become increasingly appreciated that practice effects and ceiling effects could result in type 1 or type 2 errors in clinical trials involving early stage AD populations, given the necessity of serial assessments. This proposal has the overarching goal of validating novel cognitive and everyday functional measures that have sharply attenuated practice effects and are not prone to ceiling effects for use in preclinical Alzheimer's disease (AD) trials in which participants are cognitively within normal limits. To implement this, we will conduct an innovative parallel group study in which 320 healthy, non-cognitively impaired older subjects are randomized to one of two groups based on assessment type (novel instruments vs. established) and receive three serial assessments over a one year period. We will employ this parallel group design in order to maintain the structure of a clinical trial, while pari passu, highlighting contrasts between novel and established measures and completely avoiding any interference effects between them. Our novel cognitive measures include tests of executive function, episodic memory, and processing speed combined into a single composite. Our functional measures involve computerized performance based, ecologically relevant instrumental activities. We will compare our novel No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS) against established measures that include the PACC, ADAS-Cog, and FAQ. In preliminary data our novel measures demonstrated attenuated practice effects, high test-retest reliabilities, equivalent alternate forms, and lack of ceiling effects. Moreover, we will also examine several biomarkers and markers that may increase risk for AD (e.g., APOE e4 carrier status, hippocampal atrophy and AD cortical thinning signature, family history of AD) in order to assess the sensitivity of the measures to these known biomarkers and so provide evidence for or against the validity of the cognitive and functional tests.

There are no effective drugs to prevent, delay or treat Alzheimer?s disease (AD). The 5 million Americans currently diagnosed with AD is projected to increase to 11-16 million within two decades in the absence of effective therapies. We propose to develop for use in humans, plasma based exosome biomarker assays specifically reflecting the real-time biochemical state present in brain neurons and astrocytes. This advance will allow investigators real time assessments of AD neuropathology and opportunities to monitor drug effects. (-)-Phenserine tartrate is both a proven probe able to affect AD neuropathology that is considered important in progression to dementia, and a potential therapeutic operating independently from the AD pathology targeted over the last 30 years. Anatomical and biochemical evidence from preclinical transgenic AD models and wild type mice and rats in traumatic brain injury (TBI) and anoxia models support the translation of phenserine protection of neurons from preprogrammed cell death (PPCD) unexplained by other activities of phenserine. We have developed an extended controlled release formulation of phenserine tartrate to insure successful determination of optimal dosing that maximizes preservation of neurons and expected prevention of dementia. Based on a foundation of preclinical discovery, translational research (TBI and AD trials), clinical development at NIA, and FDA assessment, we propose a phase 1b ascending dose clinical trial of four phenserine doses given daily for 12 weeks to establish a safe and tolerated dose, to characterize biomarker responses, and to interpret their significance for cellular functioning. This dose-response evaluation prepares for advancement to a phase 2 proof of concept trial. Two specific aims are proposed to achieve this goal: Aim 1 to assess the performance of the exosome biomarkers, their ability to distinguish AD pathology from not impaired, their reproducibility, and precision in older populations; Aim 2 to conduct a phase 1b ascending dose trial of phenserine in early AD. Primary safety objectives are to define a maximally tolerated dose, and determine treatment emergent adverse events. Biomarker objectives are to enable the deployment of exosomes assays as measures of AD neuropathology and phenserine?s effects on pathology. Secondary objectives are to: 1) assess potential short-term effects of phenserine on cognition; 2) inform an ensuing phase 2 proof of concept trial with exosome biomarkers, i.e., PPCD, synaptic arborization, etc. A multi- disciplinary investigator team with expertise in drug development, biomarkers of cognitive impairment, aging, and translational research for Alzheimer therapeutics is committed to the project. Outcomes will provide: 1) an estimated safe, well-tolerated phenserine dose; 2) parameter estimates for the exosome biomarkers; and 3) parameter estimates for cognitive efficacy to advance to phase 2. The proposal meets objectives of NIA PAR- 18-175, Pilot Clinical Trials for the Spectrum of Alzheimer's Disease and Age-related Cognitive Decline.

Project Summary/Abstract Practice effects and ceiling effects could result in type 1 or type 2 errors in clinical trials involving early stage AD populations, given the necessity of serial assessments. Our funded parent grant (1R01AG051346) has the overarching goal of validating novel cognitive and everyday functional measures that have sharply attenuated practice effects and are not prone to ceiling effects for use in preclinical Alzheimer's disease (AD) trials in which participants are cognitively within normal limits. To implement this, we are conducting an innovative parallel group study in which 320 healthy, non-cognitively impaired older subjects are randomized to one of two groups based on assessment type (novel vs. established instruments) and receive three serial assessments over a one-year period. We will employ this parallel group design in order to maintain the structure of a clinical trial, while pari passu, highlighting contrasts between novel and established measures and completely avoiding any interference effects between them. Our novel cognitive measures include tests of executive function, episodic memory, and processing speed combined into a single composite. Our functional measures involve computerized performance based, ecologically relevant instrumental activities. We will compare our novel No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment System (CFAS) against established measures that include the PACC, ADAS-Cog, and FAQ. Our Revision (Competing Supplement) will further test the sensitivity of the novel measures to: 1. hippocampal atrophy and cortical thinning over a one-year interval by adding an additional MR scan at the one-year endpoint of the study; and 2. Collection of additional Blood-based (BB) biomarkers at baseline and endpoint that include total-tau, and Nfl. These are related to AD pathology and in the case of Neurofilament light chain (Nfl), to neuroaxonal injury. As such these new measures should provide convergent data as to the utility of the new measures. Additionally, we will also compare the sensitivity of the novel measures to the established measures with respect to the additional data collected in this expansion of the study. We are requesting funding for the final three years of our parent R01. Thus, in AIM 1. We will assess the relationship between change from baseline to endpoint in MR measures and change in novel and established cognitive and functional measures. We predict that the change score in novel measures will be more highly associated with change in MR measures than established measures. AIM 2. A. We will assess the relationship between changes in BB biomarkers total tau and Nfl, measured at baseline and endpoint and changes in novel and established cognitive and functional measures. B. We will assess the ability of the biomarkers to predict cognitive decline. We predict that for A. and B. associations will be more robust in the novel measures group.

PROJECT SUMMARY/ABSTRACT Therapeutics to prevent, delay and treat Alzheimer?s disease (AD) remain an unmet need. Proposed herein is a regenerative medicine, systems biology approach that targets the regenerative system of the brain while simultaneously activating systems to reduce burden of AD pathology. Allopregnanolone (Allo) is a pleiotropic neurosteroid that in preclinical discovery models of AD and aging promotes neurogenesis, restores cognitive function and reduces burden of AD pathology. Mechanisms by which Allo promotes neural stem cell regeneration and restoration of cognitive function are extensively characterized with a large margin of safety. Importantly, Allo promotes regeneration of human neural stem cells in vitro. Allo is a low molecular weight neurosteroid endogenous to the brain that is blood brain barrier penetrant with abundant existing safety data in animals and humans. Completed National Institute on Aging (NIA) Phase 1 clinical trial of Allo in persons diagnosed with MCI due to AD or mild AD, indicates that the regenerative treatment regimen of once per week via intravenous infusion is well tolerated with no indications of Allo-related adverse events. MRI brain imaging for regenerative surrogate markers and cognitive testing were well tolerated and feasible in this early AD cohort. Safety and tolerability findings in women and men are consistent with outcomes of IND-enabling chronic toxicology in two species indicating no adverse outcomes following 24 weeks of once per week Allo exposure at doses exceeding those to be tested in humans by 10-fold. Based on a foundation of discovery and mechanistic preclinical research, IND-enabling studies and Phase 1 clinical development in women and men, we propose a delayed start Phase 2 clinical trial of Allo administered in a regenerative treatment regimen for 18 months, which includes a placebo-controlled period of 12 months followed by a delayed-start (open label) period of 6 months. To advance clinical development, three specific aims are proposed. Aim 1 is designed to conduct a Phase 2, randomized, placebo-controlled, delayed start group, proof of concept clinical trial of Allo in APOEe4 positive participants diagnosed with mild AD. The primary outcome measure will be rate of change in ADAS-cog14 score after 12 months. Secondary analyses will assess change from baseline to 12 months on activities of daily living assessed by ADCS-iADL, MRI volumetric outcomes, and on cognitive function as determined by CANTAB AD battery, MMSE, and CDR-SB. Aim 1 exploratory analyses will assess cognitive clinical and functional outcomes during the delayed-start period (12-18 months). Aim 2 is exploratory and designed to develop surrogate MRI-based biomarkers of hippocampal regeneration and connectivity. Aim 3 is exploratory and is designed to establish a blood-based predictive biomarker of regenerative responders and non-responders. To be explored are Allo-induced regeneration of iPSC-derived neural stem cells and mitochondrial respiration. Secondary objective is to determine the cellular population with greatest predictive accuracy using participant derived iPSCs / neural stem cells, peripheral blood mononuclear cells and CD34+ cells.